CN115607745A - Exosome program-controlled tissue repair material and preparation method thereof - Google Patents

Exosome program-controlled tissue repair material and preparation method thereof Download PDF

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CN115607745A
CN115607745A CN202211397881.6A CN202211397881A CN115607745A CN 115607745 A CN115607745 A CN 115607745A CN 202211397881 A CN202211397881 A CN 202211397881A CN 115607745 A CN115607745 A CN 115607745A
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exosome
stem cells
flexible substrate
tissue repair
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CN115607745B (en
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杜学敏
彭明星
赵启龙
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Shenzhen Institute of Advanced Technology of CAS
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    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
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Abstract

The application provides an exosome program-controlled tissue repair material, including: the flexible substrate can convert external field energy into electricity and stimulate the stem cells growing on the surface of the flexible substrate to directionally guide differentiation, so that the proportion and the content of different types of bioactive molecules in the exosome vesicles released by the flexible substrate are regulated, and the differentiated requirements of tissues and organs on the bioactive molecules at different stages of regeneration and repair of the tissues and organs are met. Compared with the existing tissue repair material based on the exosome vesicles, the exosome program-controlled tissue repair material provided by the application can be used for orderly regulating and controlling the behavior function of cells at damaged tissues and organs through the continuous and controllable release of the stem cell exosome vesicles in the outfield mediation material, so that the regeneration and repair of the tissues and organs are promoted.

Description

Exosome program-controlled tissue repair material and preparation method thereof
Technical Field
The application relates to the field of biological materials and regenerative medicine, in particular to an exosome program-controlled tissue repair material and a preparation method thereof.
Background
The tissue repair has important significance in the aspects of dealing with tissue and organ damage, aging, pathological changes and the like. In the process of tissue repair, it is necessary to orderly regulate the behavioral functions of cells involved in tissue repair. Therefore, it is crucial to create a cellular microenvironment that can orderly regulate the behavioral functions of cells. When the tissue is regenerated and repaired, the natural cell microenvironment realizes the ordered regulation and control of cell behavior functions mainly through the interaction between extracellular matrixes and cells and the interaction between cells. In particular, in cell-cell interactions, exosome vesicles are the main means of achieving cell-cell communication: the upstream cell regulates the behavior and function of the downstream cell by releasing an exosome vesicle containing bioactive molecules such as growth factors and nucleic acid fragments, and receiving and activating a specific signal channel by the downstream cell. Based on the strong cell behavior and function regulation capacity of exosome vesicles, the exosome vesicles are widely used in the field of tissue regeneration and repair in recent years. In particular, the exosome vesicles secreted by stem cells often contain more abundant cell-regulated bioactive molecules, and have a remarkable promoting effect on the regeneration and repair of various tissues and organs.
At present, the tissue repair material and strategy based on the exosome vesicle mainly load the extracted exosome vesicle on the tissue repair material, and then release the exosome vesicle in a controlled release manner to realize the regulation and control of cell behavior functions and even promote the regeneration and repair of tissues. Although such strategies have achieved good results in different areas of tissue regeneration repair, on the one hand such strategies lose the ability to continue to promote tissue repair as the loaded exosome vesicles deplete; on one hand, the different requirements of different stages of tissue regeneration and repair on bioactive molecules are difficult to match, and the types of the bioactive molecules in the exosome vesicles are difficult to regulate according to needs.
Disclosure of Invention
In view of the above, there is a need to provide an exosome programmed-control tissue repair material for orderly regulating the behavior function of cells at damaged tissues and organs and a preparation method thereof.
In order to solve the above problems, the following technical solutions are adopted in the present application:
one of the objectives of the present application, is to provide an exosome-programmed tissue-repair material,
the flexible substrate can convert external field energy into electricity and stimulate the stem cells growing on the surface of the flexible substrate to directionally guide differentiation, so that the proportion and the content of different types of bioactive molecules in the exosome vesicles released by the stem cells are regulated, and the external field energy comprises light or a magnetic field or ultrasound.
In some of these embodiments, the flexible substrate has a thickness of 50-500 μm.
In some of the embodiments, the surface topography of the flexible substrate is a planar or three-dimensional structure, and the three-dimensional structure comprises at least one of a micro-groove array, a micro-cone array and a micro-column array.
In some of these embodiments, the three-dimensional structures have dimensions ranging from 50nm to 50 μm in width, 50nm to 50 μm in height, and 50nm to 50 μm in pitch.
In some embodiments, the flexible substrate is at least one of a piezoelectric material, a photo-deformable material composite piezoelectric material, a photovoltaic material, an up-conversion material composite photovoltaic material, a photo-thermal material composite pyroelectric material, a magneto-thermal material composite pyroelectric material, and a piezoelectric ionic gel.
In some of these embodiments, the piezoelectric material comprises a piezoelectric crystal or piezoelectric ceramic or a polyvinylidene fluoride based ferroelectric polymer or piezoelectric polymer, the piezoelectric crystal comprising a quartz crystal or lithium gallate or lithium germanate or titanium germanate or lithium tantalate; the piezoelectric ceramic comprises barium titanate or lead zirconate titanate or lead meta-niobate or lead barium lithium niobate; the polyvinylidene fluoride ferroelectric polymer comprises poly (vinylidene fluoride) or poly (vinylidene fluoride-trifluoroethylene) [ P (VDF-TrFE) copolymer ] or poly (vinylidene fluoride-chlorofluoroethylene) [ P (VDF-CFE) copolymer ] or poly (vinylidene fluoride-chlorotrifluoroethylene) [ P (VDF-CTFE) copolymer ] or poly (vinylidene fluoride-hexafluoropropylene) [ P (VDF-HFP) copolymer ] or poly (vinylidene fluoride-trifluoroethylene-chlorofluoroethylene) [ P (VDF-TrFE-CFE) terpolymer ] or poly (vinylidene fluoride-trifluoroethylene-chlorotrifluoroethylene) [ P (VDF-TrFE-CTFE) terpolymer ] or poly (vinylidene fluoride-trifluoroethylene-hexafluoropropylene) [ P (VDF-TrFE-HFP) terpolymer ]; the piezoelectric polymer comprises odd nylon or polyacrylonitrile or vinylidene cyanide and a copolymer thereof or polyurea or polyphenyl cyanoether or polyvinyl chloride or polyvinyl acetate or polypropylene or polytetrafluoroethylene.
In some embodiments, the photo-deformable material composite piezoelectric material is a combination of any one of the following photo-deformable materials and the piezoelectric material; the photoinduced deformation material comprises at least one of photoinduced heterogeneous material or ferroelectric inorganic photoinduced deformation material, and the photoinduced heterogeneous material comprises at least one of azobenzene and derivatives thereof, spiropyran and derivatives thereof; the ferroelectric inorganic photoinduced deformation material comprises at least one of lead titanate, barium titanate, potassium niobate, lithium tantalate, bismuth-layer-shaped perovskite structure ferroelectric, tungsten bronze type ferroelectric, bismuth ferrite, potassium dihydrogen phosphate, ammonium trinitrate sulfate, rosette and perovskite type organic metal halide ferroelectric.
In some of these embodiments, the photovoltaic material comprises at least one of: polyacetylene, polythiophene, polyaniline, polypyrrole and derivatives and copolymers thereof.
In some embodiments, the upconversion material composite photovoltaic material is any one of the following upconversion materials and piezoelectric materials in combination; wherein the up-conversion material comprises at least one of yttrium oxide, yttrium oxysulfide, lanthanum fluoride, sodium yttrium fluoride and sodium gadolinium fluoride.
In some embodiments, the photothermal material composite pyroelectric material comprises any one of a combination of a photothermal material and a pyroelectric material; the photo-thermal material comprises at least one of carbon black, carbon nano tubes, graphene, black phosphorus, polydopamine, gold nano rods and gallium-indium alloy liquid metal; the pyroelectric material comprises at least one of polyvinylidene fluoride ferroelectric polymer and perovskite type ferroelectric ceramic, wherein the polyvinylidene fluoride ferroelectric polymer comprises at least one of poly (vinylidene fluoride), poly (vinylidene fluoride-trifluoroethylene) [ P (VDF-TrFE) copolymer ], poly (vinylidene fluoride-chlorofluoroethylene) [ P (VDF-CFE) copolymer ], poly (vinylidene fluoride-chlorotrifluoroethylene) [ P (VDF-CTFE) copolymer ], poly (vinylidene fluoride-hexafluoropropylene) [ P (VDF-HFP) copolymer ], poly (vinylidene fluoride-trifluoroethylene-chlorofluoroethylene) [ P (VDF-TrFE-CFE) terpolymer ], poly (vinylidene fluoride-trifluoroethylene-chlorotrifluoroethylene) [ P (VDF-TrFE-CTFE) terpolymer ] and poly (vinylidene fluoride-trifluoroethylene-hexafluoropropylene) [ P (VDF-TrFE-CTFE) terpolymer ], and the perovskite type ferroelectric ceramic comprises at least one of barium titanate, lead zirconium titanate, lead metaniobate and lead lithium niobate.
In some embodiments, the magnetocaloric material composite pyroelectric material is any one of the following magnetocaloric materials and pyroelectric materials in combination; wherein the magnetocaloric material comprises at least one of Ru ferroboron alloy, ferroferric oxide, iron, cobalt, nickel and gadolinium.
In some of these embodiments, the piezoelectric ionic gel material comprises at least one of polyacrylic acid and polyacrylamide composite gel, polyacrylic acid and chitosan composite gel, sodium alginate and polyacrylamide composite gel, polyacrylic acid and choline composite gel, sodium alginate and choline composite gel, methacrylic acid acylated gelatin and choline composite gel, methacrylic acid acylated hyaluronic acid and choline composite gel.
In some of these embodiments, the stem cells comprise at least one of totipotent stem cells comprising embryonic stem cells, pluripotent stem cells comprising mesenchymal stem cells, induced pluripotent stem cells, and adult pluripotent stem cells comprising at least one of corneal stem cells or neural stem cells or endothelial precursor cells or endothelial stem cells.
In some of these embodiments, the hydrogel is at least one of the following materials: alginate, chitosan, gelatin and derivatives thereof, collagen and derivatives thereof, hyaluronic acid and derivatives thereof, extracellular matrix protein and derivatives thereof, silk fibroin and derivatives thereof, agarose, carrageenan, dextran, basement membrane matrix, polycaprolactone, polyethylene glycol and derivatives thereof, propylene glycol and epoxyethyl ether block polymer, and polyvinylpyrrolidone.
In some of these embodiments, the hydrogel layer has a thickness of 50-500 μm.
The second purpose of the application is to provide a preparation method of the exosome program-controlled tissue repair material, which comprises the following steps:
preparing the flexible substrate;
growing the stem cells on the surface of the flexible substrate;
pre-crosslinking the hydrogel on the surface of the flexible substrate so as to encapsulate the stem cells on the surface of the flexible substrate, thereby obtaining the exosome programmed tissue repair material.
In some embodiments, the step of preparing the flexible substrate specifically includes the following steps: and preparing the flexible substrate by adopting a tape casting method or a spin coating method.
In some embodiments, a planar or three-dimensional structure is formed on the surface of the flexible substrate by photolithography, plasma dry etching or machining, and the three-dimensional structure comprises at least one of a micro-groove array, a micro-cone array and a micro-column array.
In some of these embodiments, the stem cells are seeded at a density of 10 3 –10 6 Cells per square centimeter.
In some embodiments, the crosslinking manner of the crosslinking is at least one of ionic crosslinking and ultraviolet crosslinking.
This application adopts above-mentioned technical scheme, its beneficial effect as follows:
the application provides an exosome program-controlled tissue repair material, including: the flexible substrate can convert external field energy into electricity and stimulate the stem cells growing on the surface of the flexible substrate to directionally guide differentiation, so that the proportion and the content of different types of bioactive molecules in the exosome vesicles released by the flexible substrate are regulated, and the differentiated requirements of tissues and organs on the bioactive molecules at different stages of regeneration and repair of the tissues and organs are met. Compared with the existing tissue repair material based on the exosome vesicles, the exosome program-controlled tissue repair material provided by the application can be used for orderly regulating and controlling the behavior function of cells at damaged tissues and organs through the continuous and controllable release of the stem cell exosome vesicles in the outfield mediated material, so that the regeneration and repair of the tissues and organs are promoted.
Drawings
In order to more clearly illustrate the technical solutions of the embodiments of the present application, the drawings needed to be used in the description of the embodiments of the present application or the prior art will be briefly described below, and it is obvious that the drawings described below are only some embodiments of the present application, and it is obvious for those skilled in the art that other drawings can be obtained according to the drawings without creative efforts.
Fig. 1 is a schematic structural diagram of an exosome programmed tissue repair material provided in an embodiment of the present application.
Fig. 2 is a flowchart of steps for applying the exosome-programmed tissue repair material provided in this embodiment.
Detailed Description
Reference will now be made in detail to embodiments of the present application, examples of which are illustrated in the accompanying drawings, wherein like or similar reference numerals refer to the same or similar elements or elements having the same or similar function throughout. The embodiments described below with reference to the drawings are exemplary and intended to be used for explaining the present application and should not be construed as limiting the present application.
In the description of the present application, it is to be understood that the terms "upper", "lower", "horizontal", "inner", "outer", and the like, indicate orientations or positional relationships based on the orientations or positional relationships shown in the drawings, are only for convenience in describing the present application and simplifying the description, and do not indicate or imply that the referred devices or elements must have a specific orientation, be constructed in a specific orientation, and be operated, and thus, should not be construed as limiting the present application.
Furthermore, the terms "first", "second" and "first" are used for descriptive purposes only and are not to be construed as indicating or implying relative importance or implicitly indicating the number of technical features indicated. Thus, a feature defined as "first" or "second" may explicitly or implicitly include one or more of that feature. In the description of the present application, "a plurality" means two or more unless specifically limited otherwise.
In order to make the objects, technical solutions and advantages of the present application more apparent, the present application is described in further detail below with reference to the accompanying drawings and embodiments.
Referring to fig. 1, a schematic structural diagram of an exosome-programmed tissue repair material provided in an embodiment of the present application includes: the stem cells 120 can sustainably release exosome vesicles containing bioactive molecules, the flexible substrate 110 can convert external field energy into electricity, and stimulate the stem cells 120 growing on the surface of the flexible substrate 110 to directionally guide differentiation, so as to regulate the proportion and content of different types of bioactive molecules in the exosome vesicles released by the stem cells 120, wherein the external field energy comprises light or a magnetic field or ultrasound of the flexible substrate.
In some of these embodiments, the flexible substrate has a thickness of 50-500 μm.
In some of the embodiments, the surface topography of the flexible substrate is a planar or three-dimensional structure, and the three-dimensional structure comprises at least one of a micro-groove array, a micro-cone array and a micro-column array.
In some of these embodiments, the three-dimensional structures have dimensions ranging from 50nm to 50 μm in width, 50nm to 50 μm in height, and 50nm to 50 μm in pitch.
In some of these embodiments, the flexible substrate is at least one of a piezoelectric material, a photo-deformable material composite piezoelectric material, a photovoltaic material, an up-conversion material composite photovoltaic material, a photo-thermal material composite pyroelectric material, a magneto-thermal material composite pyroelectric material, and a piezoelectric ionic gel.
In some of these embodiments, the piezoelectric material comprises a piezoelectric crystal or piezoelectric ceramic or a polyvinylidene fluoride based ferroelectric polymer or piezoelectric polymer, the piezoelectric crystal comprising a quartz crystal or lithium gallate or lithium germanate or titanium germanate or lithium tantalate; the piezoelectric ceramic comprises barium titanate or lead zirconate titanate or lead meta-niobate or lead barium lithium niobate; the polyvinylidene fluoride ferroelectric polymer comprises poly (vinylidene fluoride) or poly (vinylidene fluoride-trifluoroethylene) [ P (VDF-TrFE) copolymer ] or poly (vinylidene fluoride-chlorofluoroethylene) [ P (VDF-CFE) copolymer ] or poly (vinylidene fluoride-chlorotrifluoroethylene) [ P (VDF-CTFE) copolymer ] or poly (vinylidene fluoride-hexafluoropropylene) [ P (VDF-HFP) copolymer ] or poly (vinylidene fluoride-trifluoroethylene-chlorofluoroethylene) [ P (VDF-TrFE-CFE) terpolymer ] or poly (vinylidene fluoride-trifluoroethylene-chlorotrifluoroethylene) [ P (VDF-TrFE-CTFE) terpolymer ] or poly (vinylidene fluoride-trifluoroethylene-hexafluoropropylene) [ P (VDF-TrFE-CTFE) terpolymer ]; the piezoelectric polymer comprises odd nylon or polyacrylonitrile or vinylidene cyanide and a copolymer thereof or polyurea or polyphenyl cyanoether or polyvinyl chloride or polyvinyl acetate or polypropylene or polytetrafluoroethylene.
In some embodiments, the photo-deformable material composite piezoelectric material is a combination of any one of the following photo-deformable materials and the piezoelectric material; the photoinduced deformation material comprises at least one of photoinduced heterogeneous material or ferroelectric inorganic photoinduced deformation material, and the photoinduced heterogeneous material comprises at least one of azobenzene and derivatives thereof, spiropyran and derivatives thereof; the ferroelectric inorganic photoinduced deformation material comprises at least one of lead titanate, barium titanate, potassium niobate, lithium tantalate, bismuth-layer-shaped perovskite structure ferroelectric, tungsten bronze type ferroelectric, bismuth ferrite, potassium dihydrogen phosphate, ammonium trinitrate sulfate, rosette and perovskite type organic metal halide ferroelectric.
In some of these embodiments, the photovoltaic material comprises at least one of: polyacetylene, polythiophene, polyaniline, polypyrrole and derivatives and copolymers thereof.
In some embodiments, the upconversion material composite photovoltaic material is any one of the following upconversion materials and piezoelectric materials in combination; wherein the up-conversion material comprises at least one of yttrium oxide, yttrium oxysulfide, lanthanum fluoride, sodium yttrium fluoride and sodium gadolinium fluoride.
In some embodiments, the photothermal material composite pyroelectric material comprises any one combination of photothermal material and pyroelectric material; the photo-thermal material comprises at least one of carbon black, carbon nano tubes, graphene, black phosphorus, polydopamine, gold nano rods and gallium-indium alloy liquid metal; the pyroelectric material comprises at least one of polyvinylidene fluoride ferroelectric polymer and perovskite type ferroelectric ceramic, wherein the polyvinylidene fluoride ferroelectric polymer comprises at least one of poly (vinylidene fluoride), poly (vinylidene fluoride-trifluoroethylene) [ P (VDF-TrFE) copolymer ], poly (vinylidene fluoride-chlorofluoroethylene) [ P (VDF-CFE) copolymer ], poly (vinylidene fluoride-chlorotrifluoroethylene) [ P (VDF-CTFE) copolymer ], poly (vinylidene fluoride-hexafluoropropylene) [ P (VDF-HFP) copolymer ], poly (vinylidene fluoride-trifluoroethylene-chlorofluoroethylene) [ P (VDF-TrFE-CFE) terpolymer ], poly (vinylidene fluoride-trifluoroethylene-chlorotrifluoroethylene) [ P (VDF-TrFE-CTFE) terpolymer ] and poly (vinylidene fluoride-trifluoroethylene-hexafluoropropylene) [ P (VDF-TrFE-CTFE) terpolymer ], and the perovskite type ferroelectric ceramic comprises at least one of barium titanate, lead zirconium titanate, lead metaniobate and lead lithium niobate.
In some embodiments, the magnetocaloric material composite pyroelectric material is any one of the following magnetocaloric materials and pyroelectric materials in combination; wherein the magnetocaloric material comprises at least one of Ru ferroboron alloy, ferroferric oxide, iron, cobalt, nickel and gadolinium.
In some of these embodiments, the piezoelectric ionic gel material comprises at least one of polyacrylic acid and polyacrylamide composite gel, polyacrylic acid and chitosan composite gel, sodium alginate and polyacrylamide composite gel, polyacrylic acid and choline composite gel, sodium alginate and choline composite gel, methacrylic acid acylated gelatin and choline composite gel, methacrylic acid acylated hyaluronic acid and choline composite gel.
The stem cells comprise at least one of totipotent stem cells, pluripotent stem cells, induced pluripotent stem cells and adult unipotent stem cells, the totipotent stem cells comprise embryonic stem cells, the pluripotent stem cells comprise mesenchymal stem cells, and the adult unipotent stem cells comprise at least one of corneal stem cells, neural stem cells, endothelial precursor cells or endothelial stem cells.
In some of these embodiments, the hydrogel is at least one of the following materials: alginate, chitosan, gelatin and derivatives thereof, collagen and derivatives thereof, hyaluronic acid and derivatives thereof, extracellular matrix protein and derivatives thereof, silk fibroin and derivatives thereof, agarose, carrageenan, dextran, basement membrane matrix, polycaprolactone, polyethylene glycol and derivatives thereof, propylene glycol and epoxyethyl ether block polymer, and polyvinylpyrrolidone.
In some of these embodiments, the hydrogel layer has a thickness of 50-500 μm.
It will be appreciated that the above embodiments of the present application are not critical to the particular flexible substrate, stem cell and hydrogel type, and that its/their selection depends on the end use and the effect desired for that use. For example, in order to ensure the sustained release of the exosome vesicle of the stem cell with therapeutic significance, the selected functional flexible substrate and the hydrogel are required to have good biocompatibility, biodegradability and low immunogenicity; in order to realize the regulation and control of the dry cell differentiation mediated by an external field and the secretion of exosome vesicles, a functional flexible substrate is selected to generate electric stimulation with enough cell response under the excitation of the external field, and the activity of cells is not influenced.
The exosome program-controlled tissue repair material provided by the application can be used for orderly regulating and controlling the behavior function of cells at damaged tissues and organs through the continuous and controllable release of stem cell exosome vesicles in an outfield mediation material, thereby promoting the regeneration and repair of the tissues and organs.
Referring to fig. 2, a flow chart of steps of the preparation method of the exosome program-controlled tissue repair material provided in the present application includes the following steps S110 to S130, and implementation of each step is described in detail below.
Step S110: preparing the flexible substrate.
In some embodiments, the step of preparing the flexible substrate specifically includes the following steps: and preparing the flexible substrate by adopting a tape casting method or a spin coating method.
Step S120: growing the stem cells on the surface of the flexible substrate.
In some embodiments, a planar or three-dimensional structure is formed on the surface of the flexible substrate by photolithography, plasma dry etching or machining, and the three-dimensional structure comprises at least one of a micro-groove array, a micro-cone array and a micro-column array.
Further, the stem cells were seeded at a density of 10 3 –10 6 Cells per square centimeter.
Step S130: pre-crosslinking the hydrogel on the surface of the flexible substrate so as to encapsulate the stem cells on the surface of the flexible substrate, thereby obtaining the exosome programmed tissue repair material.
In some embodiments, the crosslinking manner of the crosslinking is at least one of ionic crosslinking and ultraviolet crosslinking.
Compared with the existing exosome program-controlled tissue repair material, the preparation method of the exosome program-controlled tissue repair material provided by the application does not need a complex preparation process and an integrated packaging technology, the preparation process is simple, and the prepared exosome program-controlled tissue repair material can be used for regeneration and repair of tissues and organs.
The above technical solutions of the present application will be described in detail with reference to specific examples.
Example 1
An exosome program-controlled tissue repair material based on an active interface is structurally shown in figure 1, and comprises a functional flexible substrate, stem cells growing on the functional flexible substrate in an adhesion mode, and hydrogel for stem cell encapsulation; the functional flexible substrate is made of a piezoelectric material, the stem cells are mesenchymal stem cells, and the hydrogel is calcium ion crosslinked sodium alginate.
In the embodiment, the surface appearance of the functional flexible substrate is a flat unstructured surface, the thickness of the functional flexible substrate is 50 microns, and the functional flexible substrate is made of polyvinylidene fluoride capable of generating electricity under the mediation of an ultrasonic external field; the inoculated mesenchymal stem cells are mouse bone marrow-derived mesenchymal stem cells; the hydrogel material is calcium ion crosslinked sodium alginate, and the thickness is 50 μm.
The preparation method of the exosome programmed tissue repair material based on the active interface comprises the following steps:
1) Preparing a functional flexible substrate;
preparing a polyvinylidene fluoride solution with the concentration of 10w/v% by using dimethyl sulfoxide as a solvent; casting polyvinylidene fluoride solution on the surface of the silicon wafer with a smooth surface, and drying at 80 ℃ to prepare a functional flexible substrate with a planar surface appearance; and irradiating the prepared functional flexible substrate by a cobalt source, and finishing material sterilization with the irradiation dose of 15kGy and the irradiation time of 30 minutes.
2) Stem cell inoculation;
using cell suspension of mouse bone marrow-derived mesenchymal stem cells obtained by trypsinization, and placing the cell suspension on the surface of a sterilized functional flexible substrate by 10 6 Cells were seeded at a seeding density of cells per square centimeter.
3) Hydrogel packaging;
after cells are inoculated for at least 24 hours, covering the surface of a functional flexible substrate inoculated with stem cells with 3w/v% of sodium alginate hydrogel prepolymerization solution, then dropwise adding 0.3M calcium chloride aqueous solution, and completing encapsulation hydrogel crosslinking through ionic crosslinking to obtain the exosome program-controlled tissue repair material based on the active interface.
Example 2
An exosome program-controlled tissue repair material based on an active interface is structurally shown in figure 1, and comprises a functional flexible substrate, stem cells growing on the functional flexible substrate in an adhesion mode, and hydrogel for stem cell encapsulation; the functional flexible substrate is made of a photoinduced deformation material and a piezoelectric material, the stem cells are embryonic stem cells, and the hydrogel is methacrylic acid acylated gelatin.
In the embodiment, the surface appearance of the functional flexible substrate is a micro-groove array structure (the width of the micro-groove is 50 microns, the height of the micro-groove is 50 microns, and the distance of the micro-groove is 50 microns), the thickness of the substrate material is 500 microns, and the substrate material is a polyvinylidene fluoride and azobenzene compound capable of generating electricity under the mediation of visible light irradiation; the inoculated embryonic stem cells are mouse embryonic stem cells; the hydrogel material is methacrylic acidylated gelatin, and the thickness is 500 μm.
The preparation method of the exosome programmed tissue repair material based on the active interface comprises the following steps:
1) Preparing a functional flexible substrate;
preparing a mixed solution with polyvinylidene fluoride concentration of 5w/v% and azobenzene concentration of 1w/v% by using dimethyl sulfoxide as a solvent; casting the mixed solution on the surface of a micro-groove array structure (the width of a micro-groove is 50 mu m, the height is 50 mu m, and the distance is 50 mu m) template obtained by machining, and drying at 80 ℃ to prepare a functional flexible substrate with the surface appearance of the micro-groove array; and irradiating the prepared functional flexible substrate by a cobalt source, and finishing material sterilization with the irradiation dose of 15kGy and the irradiation time of 30 minutes.
2) Stem cell inoculation;
using cell suspension of mouse embryonic stem cells obtained by trypsinization, and sterilizing the surface of the functional flexible substrate to obtain a functional flexible substrate with the thickness of 10% 4 Cells were seeded at a seeding density of cells per square centimeter.
3) Hydrogel packaging;
after cells are inoculated for at least 24 hours, 10w/v% methacrylic acid acylated gelatin hydrogel pre-polymerization liquid added with 0.1w/v%2959 photoinitiator covers the surface of the functional flexible substrate inoculated with stem cells, then the functional flexible substrate is irradiated by an ultraviolet crosslinking instrument for reaction for 10 minutes, and encapsulation hydrogel crosslinking is completed through ultraviolet crosslinking, so that the exosome program-controlled tissue repair material based on the active interface is obtained.
Example 3
An exosome program-controlled tissue repair material based on an active interface is structurally shown in figure 1, and comprises a functional flexible substrate, stem cells growing on the functional flexible substrate in an adhesion mode, and hydrogel for stem cell encapsulation; the functional flexible substrate is made of a photovoltaic material, the stem cells are induced multifunctional stem cells, and the hydrogel is calcium ion crosslinked sodium alginate.
In the embodiment, the surface appearance of the functional flexible substrate is a flat unstructured surface, the thickness of the functional flexible substrate is 50 microns, and the functional flexible substrate is made of poly-3 hexylthiophene (P3 HT) which can generate electricity under the mediation of visible light irradiation; the inoculated mouse embryonic stem cells are mouse fibroblast source induced multifunctional stem cells; the hydrogel material is calcium ion crosslinked sodium alginate, and the thickness is 50 μm.
The preparation method of the exosome programmed tissue repair material based on the active interface comprises the following steps:
1) Preparing a functional flexible substrate;
using 1,2-dichlorobenzene as a solvent to prepare a P3HT solution with the concentration of 30 mg/mL; pouring the solution on the surface of a silicon wafer with a smooth surface, and spin-coating at 60 ℃ to prepare a functional flexible substrate with a planar appearance; and irradiating the prepared functional flexible substrate by a cobalt source, and finishing material sterilization with the irradiation dose of 15kGy and the irradiation time of 30 minutes.
2) Stem cell inoculation;
the cell suspension of the pluripotent stem cells was induced using a mouse fibroblast source obtained by digestion with fetal pancreatin, and the cells were seeded at a seeding density of 103 cells/cm square on the surface of the sterilized functional flexible substrate.
3) Hydrogel packaging;
after the cells are inoculated and cultured for 24 hours, covering the surface of the functional flexible substrate inoculated with the stem cells with 3w/v% of sodium alginate hydrogel prepolymerization solution, then dropwise adding 0.3M calcium chloride aqueous solution, and completing encapsulation hydrogel crosslinking through ionic crosslinking to obtain the exosome program-controlled tissue repair material based on the active interface.
Example 4
An exosome program-controlled tissue repair material based on an active interface is structurally shown in figure 1, and comprises a functional flexible substrate, stem cells growing on the functional flexible substrate in an adhesion mode, and hydrogel for stem cell encapsulation; the functional flexible substrate is made of an up-conversion material composite photovoltaic material, the stem cells are mesenchymal stem cells, and the hydrogel is calcium ion crosslinked sodium alginate.
In the embodiment, the surface appearance of the functional flexible substrate is a flat unstructured surface, the thickness of the functional flexible substrate is 100 microns, and the functional flexible substrate is made of poly-3 hexylthiophene (P3 HT) which can generate electricity under the mediation of visible light irradiation; the inoculated mesenchymal cells are mouse bone marrow-derived mesenchymal stem cells; the hydrogel material is calcium ion crosslinked sodium alginate, and the thickness is 100 μm.
The preparation method of the exosome programmed tissue repair material based on the active interface comprises the following steps:
1) Preparing a functional flexible substrate;
preparing a mixture solution containing 30mg/mL P3HT and 0.1mg/mL sodium gadolinium fluoride using 1,2-dichlorobenzene as a solvent; pouring the solution on the surface of a silicon wafer with a smooth surface, and spin-coating at 60 ℃ to prepare a functional flexible substrate with a planar appearance; and irradiating the prepared functional flexible substrate by a cobalt source, and finishing material sterilization with the irradiation dose of 15kGy and the irradiation time of 30 minutes.
2) Stem cell inoculation;
using cell suspension of mouse bone marrow-derived mesenchymal stem cells obtained by trypsinization, and placing the cell suspension on the surface of a sterilized functional flexible substrate by 10 6 Cells were seeded at a seeding density of cells per square centimeter.
3) Hydrogel packaging;
after the cells are inoculated and cultured for 14 days, covering the surface of the functional flexible substrate inoculated with the stem cells with 3w/v% of sodium alginate hydrogel prepolymerization solution, then dropwise adding 0.3M calcium chloride aqueous solution, and completing encapsulation hydrogel crosslinking through ionic crosslinking to obtain the exosome program-controlled tissue repair material based on the active interface.
Example 5
An exosome program-controlled tissue repair material based on an active interface is structurally shown in figure 1, and comprises a functional flexible substrate, stem cells growing on the functional flexible substrate in an adhesion mode, and hydrogel for stem cell encapsulation; the functional flexible substrate is made of a photothermal material composite pyroelectric material, stem cells are mesenchymal stem cells, and hydrogel is calcium ion crosslinked sodium alginate.
In this embodiment, the surface topography of the functional flexible substrate is a surface of a micro-cone array, and the width of the micro-cone is: 5 μm, high: 5 μm, pitch: 5 μm, substrate thickness of 200 μm, and material of P (VDF-TrFE) copolymer and polydopamine composite capable of generating electricity under the mediation of near infrared light irradiation; the inoculated mesenchymal stem cells are mouse bone marrow-derived mesenchymal stem cells; the hydrogel material is calcium ion crosslinked sodium alginate, and the thickness is 200 μm.
The preparation method of the exosome programmed tissue repair material based on the active interface comprises the following steps:
1) Preparing a functional flexible substrate;
preparing a mixed solution containing 10w/v% of polyvinylidene fluoride and 0.1w/v% of polydopamine by using dimethyl sulfoxide as a solvent; casting the mixed solution on the surface of a micro-cone array structure (the width of a micro-cone is 5 mu m, the height is 5 mu m and the distance is 5 mu m) template obtained by plasma dry etching, and drying at 80 ℃ to prepare the functional flexible substrate with the surface appearance of the micro-cone array; the prepared functional flexible substrate was irradiated by a cobalt source at an irradiation dose of 15kGy for an irradiation time of 30 minutes to complete material sterilization.
2) Stem cell inoculation;
using cell suspension of mouse bone marrow-derived mesenchymal stem cells obtained by trypsinization, and placing the cell suspension on the surface of a sterilized functional flexible substrate by 10 6 Cells were seeded at a seeding density of cells/cm.
3) Hydrogel packaging;
after cells are inoculated for at least 24 hours, covering the surface of a functional flexible substrate inoculated with stem cells with 3w/v% of sodium alginate hydrogel prepolymerization solution, then dropwise adding 0.3M calcium chloride aqueous solution, and completing encapsulation hydrogel crosslinking through ionic crosslinking to obtain the exosome program-controlled tissue repair material based on the active interface.
Example 6
An exosome program-controlled tissue repair material based on an active interface is structurally shown in figure 1, and comprises a functional flexible substrate, stem cells growing on the functional flexible substrate in an adhesion mode, and hydrogel for stem cell encapsulation; the functional flexible substrate is made of a magnetocaloric material and a pyroelectric material, the stem cells are mesenchymal stem cells, and the hydrogel is calcium ion crosslinked sodium alginate.
In this embodiment, the surface topography of the functional flexible substrate is a surface of a micropillar array, the width of the micropillar: 5 μm, high: 5 μm, pitch: 5 μm, the thickness of the substrate is 50 μm, and the material is a compound of P (VDF-TrFE) copolymer and ferroferric oxide which can generate electricity under the mediation of an alternating magnetic field; the inoculated mesenchymal stem cells are mouse bone marrow-derived mesenchymal stem cells; the hydrogel material is calcium ion crosslinked sodium alginate, and the thickness is 50 μm.
The preparation method of the exosome programmed tissue repair material based on the active interface comprises the following steps:
1) Preparing a functional flexible substrate;
preparing a mixed solution containing 10w/v% of polyvinylidene fluoride and 5mg/mL ferroferric oxide nano particles by using dimethyl sulfoxide as a solvent; casting the mixed solution on the surface of a micro-column array structure (width: 5 μm, height: 5 μm, and distance: 5 μm) template obtained by photoetching to prepare a functional flexible substrate with the surface topography of the micro-column array; and irradiating the prepared functional flexible substrate by a cobalt source, and finishing material sterilization with the irradiation dose of 15kGy and the irradiation time of 30 minutes.
2) Stem cell inoculation;
using cell suspension of mouse bone marrow-derived mesenchymal stem cells obtained by trypsinization, and placing the cell suspension on the surface of a sterilized functional flexible substrate by 10 6 Cells were seeded at a seeding density of cells per square centimeter.
3) Hydrogel packaging;
after cells are inoculated for at least 24 hours, covering the surface of a functional flexible substrate inoculated with stem cells with 3w/v% of sodium alginate hydrogel prepolymerization solution, then dropwise adding 0.3M calcium chloride aqueous solution, and completing encapsulation hydrogel crosslinking through ionic crosslinking to obtain the exosome program-controlled tissue repair material based on the active interface.
Example 7
An exosome program-controlled tissue repair material based on an active interface is structurally shown in figure 1, and comprises a functional flexible substrate, stem cells growing on the functional flexible substrate in an adhesion mode, and hydrogel for stem cell encapsulation; the functional flexible substrate is made of piezoelectric ion gel materials, the stem cells are adult unipotent stem cells, and the hydrogel is calcium ion crosslinked sodium alginate.
In this embodiment, the surface topography of the functional flexible substrate is a surface of a micropillar array, the width of the micropillar: 50nm, high: 50nm, pitch: 50nm, the thickness of the substrate is 50 μm, and the material is a compound of polymethacrylic acid and choline capable of generating electricity under ultrasonic mediation; the inoculated adult unipotent stem cells are mouse neural stem cells; the hydrogel material is calcium ion crosslinked sodium alginate, and the thickness is 50 μm.
The preparation method of the exosome programmed tissue repair material based on the active interface comprises the following steps:
1) Preparing a functional flexible substrate;
preparing an aqueous solution containing 10w/v% of methacrylic acid, 3w/v% of choline chloride and 0.1w/v% of 2959 photoinitiator; casting the mixed solution on the surface of a micro-column array structure (width: 50nm, height: 50nm, and distance: 50 nm) template obtained by photoetching, and reacting for 10 minutes under the irradiation of an ultraviolet crosslinking instrument to obtain a functional flexible substrate with the surface topography of the micro-column array; and irradiating the prepared functional flexible substrate by a cobalt source, and finishing material sterilization with the irradiation dose of 15kGy and the irradiation time of 30 minutes.
2) Stem cell inoculation;
using cell suspension of mouse neural stem cells obtained by trypsinization, and placing the cell suspension on the surface of a sterilized functional flexible substrate to obtain a solution with the concentration of 10% 6 Cells were seeded at a seeding density of cells per square centimeter.
3) Hydrogel packaging;
after cells are inoculated for at least 24 hours, covering the surface of a functional flexible substrate inoculated with stem cells with 3w/v% of sodium alginate hydrogel prepolymerization solution, then dropwise adding 0.3M calcium chloride aqueous solution, and completing encapsulation hydrogel crosslinking through ionic crosslinking to obtain the exosome program-controlled tissue repair material based on the active interface.
It is to be understood that various features of the above-described embodiments may be combined in any combination, and for the sake of brevity, all possible combinations of features in the above-described embodiments may not be described in detail, but rather, all combinations of features may be considered to fall within the scope of the present disclosure unless there is a conflict between such combinations.
The foregoing is considered as illustrative only of the preferred embodiments of the invention, and is presented only for the purpose of illustrating the principles of the invention and not in any way to limit its scope. Any modifications, equivalents, and improvements made within the spirit and principles of the present application and other embodiments of the present application that one skilled in the art may recognize without inventive faculty are intended to be included within the scope of the present application.

Claims (20)

1. An exosome-programmed tissue-repair material, comprising: the flexible substrate can convert external field energy into electricity and stimulate the stem cells growing on the surface of the flexible substrate to directionally guide differentiation, so that the proportion and the content of different types of bioactive molecules in the exosome vesicles released by the stem cells are regulated, and the external field energy comprises light or a magnetic field or ultrasound.
2. An exosome-programmed tissue repair material according to claim 1, in which the flexible substrate has a thickness of 50-500 μ ι η.
3. The exosome-programmed tissue repair material according to claim 1, wherein the surface topography of the flexible substrate is a planar or three-dimensional structure comprising at least one of a micro-groove array, a micro-cone array, a micro-pillar array.
4. An active interface based exosome programmed tissue repair material according to claim 1, wherein said three-dimensional structures have dimensions of width 50nm-50 μ ι η in width, height 50nm-50 μ ι η in height and pitch 50nm-50 μ ι η.
5. An exosome programmed tissue repair material according to claim 1 or 2 or 3 or 4, wherein the flexible substrate is at least one of a piezoelectric material, a photo-deformable material composite piezoelectric material, a photovoltaic material, an up-conversion material composite photovoltaic material, a photo-thermal material composite pyroelectric material, a magneto-thermal material composite pyroelectric material, a piezoelectric ionic gel.
6. The exosome-controlled tissue repair material according to claim 5, wherein the piezoelectric material comprises a piezoelectric crystal or a piezoelectric ceramic or a polyvinylidene fluoride-based ferroelectric polymer or a piezoelectric polymer, the piezoelectric crystal comprising quartz crystal or lithium gallate or lithium germanate or titanium germanate or lithium tantalate; the piezoelectric ceramic comprises barium titanate or lead zirconate titanate or lead meta-niobate or lead barium lithium niobate; the polyvinylidene fluoride ferroelectric polymer comprises poly (vinylidene fluoride) or poly (vinylidene fluoride-trifluoroethylene) [ P (VDF-TrFE) copolymer ], or poly (vinylidene fluoride-chlorofluoroethylene) [ P (VDF-CFE) copolymer ] or poly (vinylidene fluoride-chlorotrifluoroethylene)
[ P (VDF-CTFE) copolymer ] or poly (vinylidene fluoride-hexafluoropropylene) [ P (VDF-HFP) copolymer ] or poly (vinylidene fluoride-trifluoroethylene-chlorofluoroethylene) [ P (VDF-TrFE-CFE) terpolymer ] or poly (vinylidene fluoride-trifluoroethylene-chlorotrifluoroethylene) [ P (VDF-TrFE-CTFE) terpolymer ] or poly (vinylidene fluoride-trifluoroethylene-hexafluoropropylene) [ P (VDF-TrFE-HFP) terpolymer ]; the piezoelectric polymer comprises odd nylon or polyacrylonitrile or vinylidene cyanide and a copolymer thereof or polyurea or polyphenyl cyanoether or polyvinyl chloride or polyvinyl acetate or polypropylene or polytetrafluoroethylene.
7. An exosome program-controlled tissue repair material according to claim 5 or 6, wherein the photo-deformable material composite piezoelectric material is a combination of any one of the following photo-deformable materials and the piezoelectric material; the photoinduced deformation material comprises at least one of photoinduced isomerism material or ferroelectric inorganic photoinduced deformation material, and the photoinduced isomerism material comprises at least one of azobenzene and derivatives thereof, spiropyran and derivatives thereof; the ferroelectric inorganic photoinduced deformation material comprises at least one of lead titanate, barium titanate, potassium niobate, lithium tantalate, bismuth-layer-shaped perovskite structure ferroelectric, tungsten bronze type ferroelectric, bismuth ferrite, potassium dihydrogen phosphate, ammonium trinitrate sulfate, rosette and perovskite type organic metal halide ferroelectric.
8. The exosome-programmed tissue repair material according to claim 5, wherein the photovoltaic material comprises at least one of: polyacetylene, polythiophene, polyaniline, polypyrrole and derivatives and copolymers thereof.
9. An exosome-controlled tissue-repair material according to claim 5 or 6, wherein the up-conversion material composite photovoltaic material is any one of the following up-conversion materials and the piezoelectric material in combination; wherein the up-conversion material comprises at least one of yttrium oxide, yttrium oxysulfide, lanthanum fluoride, sodium yttrium fluoride and sodium gadolinium fluoride.
10. The exosome-programmed tissue repair material according to claim 5, wherein the photothermal material composite pyroelectric material comprises any one combination of photothermal material and pyroelectric material; the photo-thermal material comprises at least one of carbon black, carbon nano tubes, graphene, black phosphorus, polydopamine, gold nano rods and gallium-indium alloy liquid metal; the pyroelectric material comprises at least one of polyvinylidene fluoride ferroelectric polymer and perovskite type ferroelectric ceramic, wherein the polyvinylidene fluoride ferroelectric polymer comprises at least one of poly (vinylidene fluoride), poly (vinylidene fluoride-trifluoroethylene) [ P (VDF-TrFE) copolymer ], poly (vinylidene fluoride-chlorofluoroethylene) [ P (VDF-CFE) copolymer ], poly (vinylidene fluoride-chlorotrifluoroethylene) [ P (VDF-CTFE) copolymer ], poly (vinylidene fluoride-hexafluoropropylene) [ P (VDF-HFP) copolymer ], poly (vinylidene fluoride-trifluoroethylene-chlorofluoroethylene) [ P (VDF-TrFE-CFE) terpolymer ], poly (vinylidene fluoride-trifluoroethylene-chlorotrifluoroethylene) [ P (VDF-TrFE-CTFE) terpolymer ] and poly (vinylidene fluoride-trifluoroethylene-hexafluoropropylene) [ P (VDF-TrFE-CTFE) terpolymer ], and the perovskite type ferroelectric ceramic comprises at least one of barium titanate, lead zirconium titanate, lead metaniobate and lead lithium niobate.
11. The exosome-controlled tissue repair material according to claim 5 or 10, wherein the magnetocaloric material composite pyroelectric material is any one of the following magnetocaloric material and the pyroelectric material in combination; wherein the magnetocaloric material comprises at least one of Ru ferroboron alloy, ferroferric oxide, iron, cobalt, nickel and gadolinium.
12. The exosome-programmed tissue repair material according to claim 5, wherein the piezoelectric ionic gel material comprises at least one of polyacrylic acid and polyacrylamide composite gel, polyacrylic acid and chitosan composite gel, sodium alginate and polyacrylamide composite gel, polyacrylic acid and choline composite gel, sodium alginate and choline composite gel, methacrylic acid acylated hyaluronic acid and choline composite gel.
13. An exosome programmed tissue repair material according to claim 1, wherein the stem cells comprise at least one of totipotent stem cells including embryonic stem cells, pluripotent stem cells including mesenchymal stem cells, induced pluripotent stem cells including at least one of corneal stem cells or neural stem cells or endothelial precursor cells or endothelial stem cells, and adult multipotent stem cells including at least one of corneal stem cells or neural stem cells or endothelial precursor cells or endothelial stem cells.
14. The exosome-programmed tissue repair material according to claim 1, wherein the hydrogel is at least one of the following: alginate, chitosan, gelatin and derivatives thereof, collagen and derivatives thereof, hyaluronic acid and derivatives thereof, extracellular matrix protein and derivatives thereof, silk fibroin and derivatives thereof, agarose, carrageenan, dextran, basement membrane matrix, polycaprolactone, polyethylene glycol and derivatives thereof, propylene glycol and epoxyethyl ether block polymer, and polyvinylpyrrolidone.
15. The exosome programmed tissue repair material according to claim 1, wherein the hydrogel layer is 50-500 μ ι η thick.
16. A method of preparing an exosome-programmed tissue repair material according to claim 1, comprising the steps of:
preparing the flexible substrate;
growing the stem cells on the surface of the flexible substrate;
pre-crosslinking the hydrogel on the surface of the flexible substrate so as to encapsulate the stem cells on the surface of the flexible substrate, thereby obtaining the exosome programmed tissue repair material.
17. The method for preparing an exosome-programmed tissue repair material according to claim 16, wherein the step of preparing the flexible substrate specifically comprises the steps of: and preparing the flexible substrate by adopting a tape casting method or a spin coating method.
18. The method of preparing an exosome-controlled tissue-repair material according to claim 16, wherein a planar or three-dimensional structure is formed on the surface of the flexible substrate by photolithography, plasma dry etching or machining, and the three-dimensional structure comprises at least one of a micro-groove array, a micro-cone array and a micro-column array.
19. The method of preparing an exosome programmed tissue repair material according to claim 16, wherein the seeding density of the stem cells is 10 3 –10 6 Cells per square centimeter.
20. The method for preparing an exosome programmed tissue repair material according to claim 16, wherein the crosslinking manner of the crosslinking is at least one of ionic crosslinking and ultraviolet crosslinking.
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